F568S

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Serine at position 568 · Lumenal loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F568 — hydrogen bond to F564

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DynaMut2 mutant · F568S

Mutant S568 — hydrogen bond to F564 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F564	F564	Preserved
Hydrogen bond	L565	L565	Preserved
Hydrogen bond	P571	P571	Preserved
Polar contact	F564	F564	Preserved
Polar contact	L565	L565	Preserved
Polar contact	F566	F566	Preserved
Polar contact	—	P571	Gained
Polar contact	I572	—	Lost
Aromatic / π	F564	—	Lost
Van der Waals	F566	—	Lost
Hydrophobic	F564	—	Lost

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

-0.75kcal/mol

Destabilising — mild

AlphaMissense

0.906

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.0013%

cDNA changec.1703T>C

ClinVar accessionVCV002080395

Last evaluated2025/12/22 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F568S Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Phenylalanine → Serine at position 568. Lumenal loop 4. ClinVar Uncertain significance, AlphaMissense 0.906, DynaMut2 ΔΔG -0.75 kcal/mol (destabilising).

Identity

Field	Value
Variant	F568S (p.Phenylalanine568Serine)
DNA change	c.1703T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002080395
Amino acid change	Phenylalanine (F) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 568	72.69 — well-folded
Domain	Lumenal loop 4
Position context	C-terminal lumenal domain · position 568 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 568 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is large aromatic hydrophobic (phenylalanine); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9063
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.75 (Destabilising)
Job ID	178092106933
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092106933

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/12/22 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F568S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.75 < 2 kcal/mol (fold intact) + AlphaMissense 0.906 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.75 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.906. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
F568S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 568 with ball-and-stick + neighbors within 5Å)
F568S_variant_card.md — this card (source of truth)
F568S_variant_card.html — styled printable card
F568S_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
F568S_wildtype_interactions.pse / F568S_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F568S PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download F568S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.